Neoantigen-based dendritic cell vaccines in lung cancer: overcoming immunosuppressive barriers for durable antitumor immunity.

Advancing together and moving forward: Combination gene and cellular immunotherapies

SUMMARYTreatments aiming to augment immune checkpoint blockade (ICB) in cancer often focus on T cell immunity, but innate immune cells may have important roles to play. Here, we demonstrate a single-dose combination treatment (termed AIP) using a pan-tumor-targeting antibody surrogate, half-life-extended interleukin-2 (IL-2), and anti-programmed cell death 1 (PD-1), which primes tumors to respond to subsequent ICB and promotes rejection of large established tumors in mice. Natural killer (NK) cells and macrophages activated by AIP treatment underwent transcriptional reprogramming; rapidly killed cancer cells; governed the recruitment of cross-presenting dendritic cells (DCs) and other leukocytes; and induced normalization of the tumor vasculature, facilitating further immune infiltration. Thus, innate cell-activating therapies can initiate critical steps leading to a self-sustaining cycle of T cell priming driven by ICB.

Introduction:Aging is the biggest cancer risk, and immune checkpoint (IC) inhibition (ICI) is a revolutionary cancer immunotherapy approach. Nonetheless, there are limited preclinical/clinical data regarding aging effects on ICI outcomes or age effects on IC expression in different organs or tumors.Methods:Flow cytometry assessed IC on immune and non-immune cells in various organs in young and aged BL6 mice. Comparisons: aged versus young naïve WT versus interferon-γKO mice and WT challenged with B16F10 melanoma and treated with αPD-1 or αPD-L1 ICI. We co-cultured young and aged T cells and myeloid cells in vitro and used OMIQ analyses to test cell–cell interactions.Results:αPD-1 ICI treated melanoma in young and aged hosts, whereas αPD-L1 ICI was only effective in young. We found considerable, previously undescribed age effects on expression of various IC molecules participating in the ICI treatment, including PD-1, PD-L1, PD-L2, and CD80, in distinct organs and in the tumor. These data help explain differential ICI efficacy in young and aged hosts. Host interferon-γ influenced age effects on IC expression in both directions depending on specific IC molecule and tissue. IC expression was further affected by tumor challenge on immune, non-immune, and tumor cells in tumor and other organs. In in vitro co-culture, αPD-1 versus αPD-L1 distinctly influenced polyclonal T cells in young versus aged, suggesting mechanisms for distinct age-related ICI outcomes.Conclusion:Age affects IC expression on specific immune cells in an organ- and tissue-specific manner. ICs were generally higher on aged immune cells. High immune-cell PD-1 could help explain αPD-1 efficacy in aged. High co-expression of CD80 with PD-L1 on dendritic cells could help explain lack of αPD-L1 efficacy in aged hosts. Factors other than myeloid cells and interferon-γ also affect age-related IC expression and T cell function, meriting additional studies.

Topical imiquimod and cryotherapy in combination with systemic immunotherapy in unresectable stage IIIC melanoma

Tumor Protection Following Vaccination With Low Doses of Lentivirally Transduced DCs Expressing the Self-antigen erbB2

BackgroundCancer peptide vaccines show only marginal effects against cancers. Immune checkpoint inhibitors (ICIs) show significant curative effects in certain types of cancers, but the response rate is still limited. In this study, we aim to improve cancer peptide vaccination by targeting Ag peptides selectively to a dendritic cell (DC) subset, XCR1-expressing DCs (XCR1+ DCs), with high ability to support CD8+ T-cell responses.MethodsWe have generated a fusion protein, consisting of an Ag peptide presented with MHC class I, and an XCR1 ligand, XCL1, and examined its effects on antitumour immunity in mice.ResultsThe fusion protein was delivered to XCR1+ DCs in an XCR1-dependent manner. Immunisation with the fusion protein plus an immune adjuvant, polyinosinic:polycytidylic acids (poly(I:C)), more potently induced Ag-specific CD8+ T-cell responses through XCR1 than the Ag peptide plus poly(I:C) or the Ag protein plus poly(I:C). The fusion protein plus poly(I:C) inhibited the tumour growth efficiently in the prophylactic and therapeutic tumour models. Furthermore, the fusion protein plus poly(I:C) showed suppressive effects on tumour growth in synergy with anti-PD-1 Ab.ConclusionsCancer Ag targeting to XCR1+ DCs should be a promising procedure as a combination anticancer therapy with immune checkpoint blockade.

Next Generation Immunotherapies – Emerging Strategies for Immune Modulation against Cancer, Infections, and Beyond

SY26-03: Immune effects of targeted therapy and implications for combination strategies

Immunotherapy in cancer is facing a revolution with the advent of immune-checkpoint inhibitors (ICI).

Immunotherapy, particularly immune checkpoint inhibitors (ICIs) programmed death-ligand 1/programmed death-1 (PD-L1/PD-1) and cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4), has heralded a new era of tumor treatment. Although ICIs have clinical benefits, their complex heterogeneity and diverse resistance mechanisms critically limit their efficacy. Neoantigens, arising from tumor-specific alterations, offer novel targets for individualized immunotherapy, because of their high immunogenicity and tumor specificity. In the past decade, neoantigen-based tumor vaccines have been demonstrated to be a promising immunotherapy strategy to prime the tumor-specific immune response. These therapeutic vaccines include peptide vaccines, nucleic acid vaccines, and dendritic cell (DC) vaccines, and are categorized according to the neoantigen source and delivery method. In vivo, neoantigens are processed and presented by antigen-presenting cells (APCs) via the peptide-Major Histocompatibility Complex (pMHC) for T cell recognition, thereby triggering specific immune responses. Because DCs, the most potent APCs, play crucial roles in antitumor immunity, neoantigen-based DC vaccines provide a promising therapeutic strategy. A series of global clinical trials are exploring the safety, feasibility, and efficacy of neoantigen-based DC vaccines in tumors. This review focuses on current progress in clinical research on neoantigen-based DC vaccines in the treatment of solid tumors.

2018 Nobel Prize in medicine awarded to cancer immunotherapy: Immune checkpoint blockade – A personal account

Liver toxicity as a limiting factor to the increasing use of immune checkpoint inhibitors.

Accumulation of extracellular adenosine within the microenvironment is a strategy exploited by tumors to escape detection by the immune system. Adenosine signaling through the adenosine 2A receptor (A2AR) on immune cells elicits a range of immunosuppressive effects which promote tumor growth and limit the efficacy of immune checkpoint inhibitors. Preclinical data with A2AR inhibitors have demonstrated tumor regressions in mouse models by rescuing T cell function; however, the mechanism and role on other immune cells has not been fully elucidated.MethodsWe report here the development of a small molecule A2AR inhibitor including characterization of binding and inhibition of A2AR function with varying amounts of a stable version of adenosine. Functional activity was tested in both mouse and human T cells and dendritic cells (DCs) in in vitro assays to understand the intrinsic role on each cell type. The role of adenosine and A2AR inhibition was tested in DC differentiation assays as well as co-culture assays to access the cross-priming function of DCs. Syngeneic models were used to assess tumor growth alone and in combination with alphaprogrammed death-ligand 1 (αPD-L1). Immunophenotyping by flow cytometry was performed to examine global immune cell changes upon A2AR inhibition.ResultsWe provide the first report of AZD4635, a novel small molecule A2AR antagonist which inhibits downstream signaling and increases T cell function as well as a novel mechanism of enhancing antigen presentation by CD103+ DCs. The role of antigen presentation by DCs, particularly CD103+ DCs, is critical to drive antitumor immunity providing rational to combine a priming agent AZD4635 with check point blockade. We find adenosine impairs the maturation and antigen presentation function of CD103+ DCs. We show in multiple syngeneic mouse tumor models that treatment of AZD4635 alone and in combination with αPD-L1 led to decreased tumor volume correlating with enhanced CD103+ function and T cell response. We extend these studies into human DCs to show that adenosine promotes a tolerogenic phenotype that can be reversed with AZD4635 restoring antigen-specific T cell activation. Our results support the novel role of adenosine signaling as an intrinsic negative regulator of CD103+ DCs maturation and priming. We show that potent inhibition of A2AR with AZD4635 reduces tumor burden and enhances antitumor immunity. This unique mechanism of action in CD103+ DCs may contribute to clinical responses as AZD4635 is being evaluated in clinical trials with IMFINZI (durvalumab, αPD-L1) in patients with solid malignancies.ConclusionWe provide evidence implicating suppression of adaptive and innate immunity by adenosine as a mechanism for immune evasion by tumors. Inhibition of adenosine signaling through selective small molecule inhibition of A2AR using AZD4635 restores T cell function via an internal mechanism as well as tumor antigen cross-presentation by CD103+ DCs resulting in antitumor immunity.

BackgroundDysfunctional antigen presentation mediated by MHC downregulation in tumor cells and low infiltration of functional professional antigen presenting cells (APCs) are critical immune evasion mechanisms underlying intrinsic resistance to immunotherapies....

The development of neoantigen-based cancer vaccines has emerged as a groundbreaking approach in the field of personalized oncology. Neoantigens, originating from tumor-specific somatic mutations, possess considerable immunogenic potential and are absent in normal tissues, making them ideal candidates for eliciting targeted and enduring anti-tumor immune responses. Progress in next-generation sequencing, immunopeptidomics, and computational epitope prediction, has accelerated the identification and prioritization of patient-specific neoantigens, thereby facilitating the development of diverse vaccine platforms, including peptide, mRNA, DNA, and dendritic cell-based formulations. Initial clinical trials have demonstrated the safety, practicality, and immunogenicity of neoantigen vaccines in various cancers, producing promising therapeutic responses, particularly when combined with immune checkpoint inhibitors. Despite these advancements, substantial challenges-such as tumor heterogeneity, the accuracy of neoantigen prediction, immune evasion mechanisms, and manufacturing complexities-continue in impede widespread clinical application. This study provides a comprehensive analysis of neoantigen biology, advanced detection technologies, and delivery platforms, while meticulously assessing clinical outcomes, combinatorial strategies, and existing limitations. It also highlights new opportunities, such as the use of artificial intelligence and the mass production of vaccines. Neoantigen-based vaccines represent a significant breakthrough in cancer immunotherapy, offering highly individualized, tumor-targeted treatment strategies that could improve long-term patient survival.